Biology subjects

Christmas, M. J.

Publications and source records attributed to Christmas, M. J..

4 recordsLinked to original sources

bioRxiv2024

Interpreting mammalian evolutionary constraint at synonymous sites in light of the unwanted transcript hypothesis

The unwanted transcript hypothesis presents a potential explanation for cryptic evolutionary constraint at synonymous sites in species with low effective population sizes, such as humans and other mammals. Selection for higher GC content and against mutations that alter splicing in native transcripts is predicted to shape synonymous site content and protect against unwanted transcripts. Here, we interpret mammalian synonymous site constraint in this context. Utilising the largest alignment of 240 placental mammal genomes and single-base resolution constraint scores, we show that 20.8% of four-fold degenerate sites are under significant constraint across mammals. There is a strong bias for guanine (G) and cytosine (C) at constrained sites, marked constraint near splice sites, and variation in human populations shows a bias against mutations that reduce synonymous site GC content. We find evidence for higher constraint on four-fold degenerate sites in species with small historic effective population sizes and high young transposable element genome content. Genes enriched for synonymous site constraint, including those forming CpG sites, are tightly regulated and integral to organismal viability through their involvement in embryo development and transcriptional regulation.

evolutionary biology↗

bioRxiv2023

Title: Leveraging Base Pair Mammalian Constraint to Understand Genetic Variation and Human Disease

Although thousands of genomic regions have been associated with heritable human diseases, attempts to elucidate biological mechanisms are impeded by a general inability to discern which genomic positions are functionally important. Evolutionary constraint is a powerful predictor of function that is agnostic to cell type or disease mechanism. Here, single base phyloP scores from the whole genome alignment of 240 placental mammals identified 3.5% of the human genome as significantly constrained, and likely functional. We compared these scores to large-scale genome annotation, genome-wide association studies (GWAS), copy number variation, clinical genetics findings, and cancer data sets. Evolutionarily constrained positions are enriched for variants explaining common disease heritability (more than any other functional annotation). Our results improve variant annotation but also highlight that the regulatory landscape of the human genome still needs to be further explored and linked to disease.

genomics↗

bioRxiv2023

Evolutionary constraint and innovation across hundreds of placental mammals

Evolutionary constraint and acceleration are powerful, cell-type agnostic measures of functional importance. Previous studies in mammals were limited by species number and reliance on human-referenced alignments. We explore the evolution of placental mammals, including humans, through reference-free whole-genome alignment of 240 species and protein-coding alignments for 428 species. We estimate 10.7% of the human genome is evolutionarily constrained. We resolve constraint to single nucleotides, pinpointing functional positions, and refine and expand by over seven-fold the catalog of ultraconserved elements. Overall, 48.5% of constrained bases are as yet unannotated, suggesting yet-to-be-discovered functional importance. Using species-level phenotypes and an updated phylogeny, we associate coding and regulatory variation with olfaction and hibernation. Focusing on biodiversity conservation, we identify genomic metrics that predict species at risk of extinction.

genomics↗

bioRxiv2021

Genome sequencing and morphometric analysis of alpine bumblebees experiencing climate change reveal ongoing phenotypic shifts and a lack of population structure

Over the last six decades, populations of the bumblebees Bombus sylvicola and Bombus balteatus in Colorado have experienced decreases in tongue length, a trait important for plant-pollinator mutualisms. It has been hypothesized that this observation reflects selection resulting from shifts in floral composition under climate change. Here we used morphometrics and population genomics to determine whether morphological change is ongoing, investigate the genetic basis of morphological variation, and analyze population structure in these populations. We generated a genome assembly of B. balteatus. We then analyzed whole-genome sequencing data and morphometric measurements of 580 samples of both species from seven high-altitude localities. Out of 281 samples originally identified as B. sylvicola, 67 formed a separate genetic cluster comprising a newly-discovered cryptic species ("incognitus"). However, an absence of genetic structure within species suggests that gene flow is common between mountains. We found a significant decrease in tongue length between bees collected between 2012-2014 and in 2017, indicating that morphological shifts are ongoing. We did not discover any genetic associations with tongue length, but a SNP related to production of a proteolytic digestive enzyme was implicated in body size variation. We identified evidence of covariance between kinship and both tongue length and body size, which is suggestive of a genetic component of these traits, although it is possible that shared environmental effects between colonies are responsible. Our results provide evidence for ongoing modification of a morphological trait important for pollination and indicate that this trait likely has a complex genetic and environmental basis.

evolutionary biology↗